Keratoconjunctivitis sicca, also known as dry eye disease or dysfunctional tear syndrome, is today understood as a multifunctional disorder of the tear film and of the ocular surface which results in discomfort, visual disturbance, and often even in ocular surface damage caused by tear film instability. Its prevalence differs widely by regions and is estimated to range from about 7.4% in the USA to about 33% in Japan (J. L. Gayton, Clinical Ophthalmology 2009:3, 405-412). According to another estimate, approximately 3.2 million women and 1.05 million men suffer from keratoconjunctivitis sicca in the USA alone. If symptomatically mild cases are also considered, there could be as many as 20 million affected people in the USA.
The main physiological function of the tear film is the lubrication of the ocular surface and the inner eyelid. In addition, it supplies the ocular surface with the nutrients which it requires, provides a smooth and regular optical surface for the eye. Moreover, it protects the ocular surface against pathogens by various mechanisms, including mechanical removal of foreign particles but also through antimicrobial substances which it contains.
The tear film is composed of a mucous component, an aqueous component, and a lipid component. The inner layer of the film is the mucous layer or component, which is bound to the ocular epithelium via the interaction of mucin molecules which are produced by conjunctival goblet cells and by stratified squameous cells of the conjunctiva and the cornea. The lubricating effect of the tear film is substantially based on the mucous layer and its composition.
On top of the mucous layer is the aqueous layer which is produced by the main and accessory lacrimal glands. Its primary function is to hydrate the mucous component and contribute to the transport of nutrients, electrolytes, antibacterial compounds, and oxygen to the ocular surface. The aqueous component contains water, electrolytes, lysozyme, lactoferrin, immunoglobulins in particular IgA), retinol, hepatocyte growth factor, epidermal growth factor as its important constituents.
The lipid layer which covers the aqueous layer is produced by the tarsal glands which are positioned at the tarsal plates of the eyelids, and to some degree also by the glands of Zeis which open into the eyelash follicles. Its functions include the enhancement of the spreading of the tear film, decrease of water loss from the aqueous layer by reducing evaporation, and preventing tear film contamination.
It is today acknowledged that keratoconjunctivitis sicca is a complex, multifunctional disorders involving several interacting pathophysiological mechanisms which are only beginning to be understood (H. D. Perry, Am. J. Man. Care 13:3, S79-S87, 2008). The two mechanisms that are being discussed as pivotal in the etiology of the disease and which also appear to reinforce each other mutually are tear hyperosmolarity and tear film instability. Hyperosmolar tear fluid can result from excessive tear film evaporation or reduced aqueous flow. It activates an inflammatory cascade and causes the release of inflammatory mediators into the tear fluid, with multiple pathophysiological effects eventually leading to increased tear film evaporation and tear film instability. Thus, tear film instability can be a consequence of hyperosmolarity. Alternatively, it can develop as the original etiological pathway, e.g. via abnormalities of the lipid layer composition, such as in tarsal gland disease).
Once keratoconjunctivitis sicca has become manifest, inflammation is one of the key processes that maintain and potentially progress the disease. Depending on the severity of the condition, patients often develop a reversible squameous metaphase and punctate erosions of the ocular epithelium. Secondary diseases whose development may be triggered by keratoconjunctivitis sicca include filamentary keratitis, microbial keratitis, corneal neovascularisation, and ocular surface keratinisation.
Two major categories of keratoconjunctivitis sicca or dry eye disease (DED) are distinguished today, which are aqueous-deficient DED and evaporative DED. Within the class of aqueous-deficient forms of DED, two major subtypes are differentiated, Sjögren and non-Sjögren. Sjögren syndrome patients suffer from autoimmune disorders in which the lacrimal glands are invaded by activated T-cells, which leads not only to keratoconjunctivitis sicca but also to a dry mouth condition. The Sjögren syndrome can be a primary disease or result from other autoimmune diseases such as systemic lupus erythrematosus or rheumathroid arthritis. Non-Sjögren patients suffering from an aqueous-deficient DED usually have a lacrimal gland insufficiency, lacrimal duct obstruction or reflex hyposecretion. The second major class, evaporative DED, is also somewhat heterogeneous and can develop as a result of diverse root causes. One of the major causes is meibomian gland disease, eyelid aperture disorders, blink disorders (as in Parkinson disease) or ocular surface disorders (as in allergic conjunctivitis).
Among the many risk factors for keratoconjunctivitis sicca that are known today, some of the best studied ones are advanced age and female sex. It appears that in particular postmenopausal women have a reduced tear production, probably related to hormonal effects which are not very well understood as yet. Further risk factors include diets with low omega-3-fatty acids, occupational factors (e.g. associated with reduced blink frequency), environmental conditions, contact lens wearing, certain systemic (anticholinergics, beta-blockers, isotretinoin, interferons, hormones) and ophthalmic medications (any frequently administered eye drops including artificial tears; especially formulations comprising preservatives), and a number of primary diseases such as Parkinson disease, hepatitis C, HIV infection, and diabetes mellitus.
The management of keratoconjunctivitis sicca relies on both non-pharmacological and pharmacological approaches and the therapeutic options depend significantly on the severity of the disease state (M. A. Lemp, Am. J. Man. Care 14:3, S88-S101, 2008). Non-pharmacological approaches may be used initially when only mild symptoms occur, or as palliative measures to support medical interventions. They include the avoidance of exacerbating factors such as dry air, wind and drafts, tobacco smoke, modification of working habits; eye lid hygiene; tear supplementation, and physical tear retention by punctal plugs or therapeutic contact lenses.
The mainstay of non-pharmacological DED treatment is the use of artificial tears for tear substitution. Most of the available products are designed as lubricants. In addition, they may function as carriers for nutrients and electrolytes (importantly, potassium and bicarbonate), and some products attempt to correct physical parameters such as an increased osmolarity in certain forms of DED. The major functional component of artificial tear compositions is an agent which increases or adjusts the viscosity and which at the same time exhibits lubricant functionality. Common compounds used for this purpose include carboxymethylcellulose and its sodium salt CCMC, carmellose), polyvinyl alcohol, hydroxypropyl methylcellulose (HPMC, hypromellose), hyaluronic acid and its sodium salt, and hydroxypropyl guar gum. However, compositions with a relatively high viscosity, and in particular gel-type formulations, have a tendency to cause visual blurring.
Some artificial tears comprise lipids to substitute for the lipid component of the natural tear film. Unfortunately, the commonly used lipids are physically and biochemically poorly related to native lipid compositions: they are based on castor oil or even mineral oil. It is intended to thereby decrease the rate of tear fluid evaporation. The same effect may perhaps also be achieved by hydrocolloids which exhibit some degree of bioadhesiveness, such as hydroxypropyl guar gum or hyaluronic acid.
At least in earlier years, multi-dose formulations for ophthalmic administration had to be preserved using a physiologically acceptable preservative in order to reduce the risk of microbial contamination and infection. Most preservatives are however problematic for DED patients in that they have a potential to negatively affect the ocular surface, thus counteracting the therapeutic intent. As an alternative, single-dose containers for the administration of non-preserved formulations were developed. These are however less convenient to handle than the conventional multi-dose bottles.
For moderate to severe forms of keratoconjunctivitis sicca, non-pharmacological approaches are not normally sufficient to manage the symptoms adequately. However, there are presently not many pharmacological therapies available which have proven to be effective and/or which have been authorised by the regulatory agencies.
Cholinergic agents such as muscarinic acetylcholine receptor antagonists may be used in aqueous deficient patient as secretagogues to stimulate tear production. An agent that has been tested successfully in several clinical studies with Sjögren syndrome patients is pilocarpine. The drug given orally at doses of 5 to 7.5 mg QID (Lemp, ditto) significantly improved DED symptoms. However, the product has not been approved by any major regulatory agencies for the use in keratoconjunctivitis sicca, neither as an oral formulation nor in the form of eye drops as they are available for the treatment of glaucoma.
Cevimeline is another parasympathomimetic drug and muscarinic agonist. It acts particularly on muscarinic M3 receptors. It is available in a few countries as an oral formulation and used in the treatment of dry mouth associated with Sjögren's syndrome. Clinical studies indicate that it is also effective in the management of symptoms associated with keratoconjunctivitis sicca of the Sjögren type, for which it is being used off-label like pilocarpine.
Anti-inflammatory agents may be used to intervene in the viscous circle of symptoms causing inflammatory response which in turn increase symptom severity. The rationale of using such agents is not restricted to aqueous deficient or even Sjögren syndrome patients. Both topical corticosteroids and topical non-steroidal anti-inflammatory (NSAID) compounds have been proposed as treatment options.
From the clinical studies that have been conducted so far (Lemp, ditto.) it appears that corticosteroids such as loteprednol etabonate and prednisolone acetate are more effective in the control of several DED symptoms than NSAIDs such as diclofenac and ketorolac. However, they are generally recommended only for short-term use. In the long term, they may cause or support the development of ocular infections, glaucoma, and cataracts. Both loteprednol etabonate and prednisolone acetate are poorly water-soluble and thus formulated as a suspension, which may be considered a disadvantage in view of the symptoms of keratoconjunctivitis sicca.
Moreover, clinical studies with, and the off-label use of, oral tetracyclines such as doxycyclin, minocycline and oxytetracycline for keratoconjunctivitis sicca have been reported (Lemp, ditto.). It is assumed that they are not primarily effective on the basis of their antibacterial properties, but due to their anti-inflammatory activity.
At least in the USA, the major pharmacological treatment option for moderate to severe keratoconjunctivitis sicca is ciclosporin (i.e. ciclosporin A, also known as cyclosporine A), which is an approved medicine in the form of an ophthalmic emulsion (Restasis®) for increasing “ . . . tear production in patients whose tear production is presumed to be suppressed due to ocular inflammation associated with keratoconjunctivitis sicca.” (Restasis prescribing information). According to the evidence that is available, topical ciclosporin is probably disease-modifying rather than only palliative. It acts as an antagonist in various inflammatory processes and cascades. For example, it reduces conjunctival interleukin-6 (IL-6) levels, decreases activated lymphocytes in the conjunctiva, suppresses other conjunctival inflammatory and apoptotic markers, and increases the number of goblet cells in the conjunctiva (Lemp, ditto.).
Ciclosporin (IUPAC name: (E)-14,17,26,32-tetrabutyl-5-ethyl-8-(1-hydroxy-2-methylhex-4-enyl)-1,3,9,12,15,18,20,23,27-nonamethyl-11,29-dipropyl-1,3,6,9,12,15,18,21,24,27,30-undecaazacyclodotriacontan-2,4,7,10,13,16,19,22,25,28,31-undecaone; C62H111N11O12; MW1202.61) is a cyclic nonribosomal peptide of 11 amino acids, originally discovered as a product of the fungus Beauveria nivea. It is an immunosuppressant drug widely used in post-allergenic organ transplant to reduce the activity of the patient's immune system and, so, the risk of organ rejection.
Ciclosporin is thought to bind to the cytosolic protein cyclophilin (immunophilin) of immunocompetent lymphocytes, especially T-lymphocytes. This complex of ciclosporin and cyclophilin inhibits calcineurin, which, under normal circumstances, is responsible for activating the transcription of interleukin 2. It also inhibits lymphokine production and interleukin release and, therefore, leads to a reduced function of effector T-cells.
Other immunosuppressant drugs with similar activity include tacrolimus, pimecrolimus, everolimus, sirolimus, deforolimus, temsirolimus, and zotarolimus, abetimus, gusperimus, and mycophenolic acid. Based on pharmacological considerations, it is presumed that these compounds would also be beneficial in the management of diseases or symptoms which are controlled by ciclosporin, such as dry eye disease or keratoconjunctivitis sicca.
Macrolide immunosuppressants such as ciclosporin, tacrolimus, sirolimus, everolimus and the like, while being highly active once they have been effectively delivered into the organism or to the target tissue, are challenging compounds to formulate and deliver to the site of action, in particular due to their extremely poor solubility and relatively large molecular size. For systemic therapy via the oral or intravenous routes of administration, they are typically presented as solubilised formulations comprising substantial amounts of solubilising excipients, such as surfactants and organic solvents.
The ophthalmic product, Restasis, which comprises ciclosporin at a concentration of 0.05%, is formulated as a sterile, preservative-free oil-in-water (o/w) emulsion. The formulation is white opaque to slightly translucent presented in single-use LDPE vials filled with 0.4 mL liquid. As inactive ingredients, it contains glycerine, castor oil, polysorbate 80, carbomer 1342, purified water and sodium hydroxide to adjust the pH to 6.5 to 8.0. The active ingredient is dissolved in the dispersed oily phase of the emulsion consisting of castor oil. It is assumed that the amphiphilic polysorbate 80 and probably also the carbomer act as stabilisers of the emulsion. The major adverse effects of Restasis include ocular burning and stinging, occurring in a phase III trial at a frequency of 14.7% and 3.4%, respectively. Other events reported in 1 to 5% of the patients include conjunctival hyperaemia, discharge, epiphora, eye pain, foreign body sensation, pruritus, and visual disturbance which is typically blurring (Restasis Prescribing Information).
Other ophthalmic formulations of ciclosporin are known from U.S. Pat. No. 5,411,952 and U.S. Pat. No. 4,839,342. The latter discloses a 2% solution of ciclosporin in olive oil, whereas U.S. Pat. No. 5,411,952 also describes solutions of ciclosporin in corn oil.
One of the disadvantages of all oil-based formulations for ophthalmic administration is that inherently have a negative impact on vision. Whether used as oily solutions or oil-in-water emulsions, they exhibit a refractive index which differs substantially from that of physiological tear fluid, which leads to visual disturbances and blurring.
Moreover, oil-based formulations do not readily mix with tear fluid to form a homogenous liquid phase. Oily solutions are altogether immiscible with the aqueous tear fluid, and the exact fate of an emulsion mixed with tear fluid in a physiological setting is not completely predictable.
Oil-in-water emulsions of poorly water-soluble drugs like ciclosporin further exhibit the disadvantage that they have a limited drug load capacity. While the active ingredient may have some solubility in the oil phase, this phase is only dispersed in the coherent aqueous phase of the emulsion so that the maximum overall drug concentration in the formulation is very limited.
In contrast to single phase systems such as aqueous or oily solutions, oil-in-water emulsions are also more complex and difficult to manufacture, especially in sterile form. Frequently, emulsions are not readily sterilisable by thermal treatment without negative impact on the physical properties of the emulsion. On the other hand, aseptic processing is complex, costly, and is associated with higher risks of failure, i.e. microbial contamination of the product.
Furthermore, oil-in-water emulsions are like aqueous solutions prone to microbial contamination during use. If they were to be presented in multi-dose containers which are in principle more cost-efficient and convenient for patients than single-use vials, they would have to be preserved in order to ensure their microbiological quality. At the same time, preservatives which can be used in ophthalmic formulations are potentially damaging to the eye, in particular to the ocular surface, and should be avoided in the context of dry eye disease.
WO 2005/123035 discloses hydrophobic compositions which may be useful as ophthalmic drug formulations. The compositions may be used to treat various ophthalmic diseases and conditions including dry eye syndrome and may comprise a therapeutic agent selected from various different therapeutic categories such as antibiotics, antimicrobials, antifungal agents, antiviral agents, antiparasitic agents, antiallergic agents, anti-inflammatory agents, alkylating agents, beta-blockers, cholinergic agents, vasoconstrictors, pupil size management agents, glaucoma agents, macular degeneration agents, and agents to arrest the development of cataracts. The hydrophobicity of the composition is achieved by selecting a hydrophobic liquid vehicle, selected in particular from silicon polymers, fluorinated silicon polymers, perfluorocarbons, fluorinated alcohols, and perfluorinated polyethers, and mixtures thereof. However, the only specific composition disclosed in the document does not incorporate an active ingredient, but is merely a vehicle consisting of a mixture of two silicon polymers, namely dimethicone and cyclomethicone, which have been combined so as to yield a viscosity of about 8,000 centistokes.
U.S. Pat. No. 6,262,126 discloses semifluorinated alkanes and their preparation, and proposes their use as vehicles in ophthalmic preparations. However, it does not disclose any specific compositions comprising a semifluorinated alkane and an incorporated active ingredient. Neither does it mention the treatment of dry eye syndrome or the incorporation of a macrolide immunosuppressant. It is also silent about ophthalmic vehicles comprising mixtures of semifluorinated alkanes and cosolvents.
It is there an object of the present invention to provide a novel pharmaceutical composition which is useful in the treatment of keratoconjunctivitis sicca, and which at the same time addresses these issues and overcomes at least one of the limitations or disadvantages associated with prior art formulations. In a specific aspect, it is an object of the invention to provide an ophthalmic composition which has the capacity to incorporate substantial amounts of poorly water-soluble drug substances useful in the management of keratoconjunctivitis sicca. In a further aspect, it is an object of the invention to provide a pharmaceutical kit comprising a composition for the treatment of keratoconjunctivitis sicca which does not exhibit one or more of the disadvantages of prior art. Further objects of the invention will become clear on the basis of the following description, examples, and patent claims.